Inhibition of the hypercapnic ventilatory response by adenosine in the retrotrapezoid nucleus in awake rats

Neuropharmacology. 2018 Aug;138:47-56. doi: 10.1016/j.neuropharm.2018.05.029. Epub 2018 May 23.


The brain regulates breathing in response to changes in tissue CO2/H+ via a process called central chemoreception. Neurons and astrocytes in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors. The role of astrocytes in this process appears to involve CO2/H+-dependent release of ATP to enhance activity of chemosensitive RTN neurons. Considering that in most brain regions extracellular ATP is rapidly broken down to adenosine by ectonucleotidase activity and since adenosine is a potent neuromodulator, we wondered whether adenosine signaling contributes to RTN chemoreceptor function. To explore this possibility, we pharmacologically manipulated activity of adenosine receptors in the RTN under control conditions and during inhalation of 7-10% CO2 (hypercapnia). In urethane-anesthetized or unrestrained conscious rats, bilateral injections of adenosine into the RTN blunted the hypercapnia ventilatory response. The inhibitory effect of adenosine on breathing was blunted by prior RTN injection of a broad spectrum adenosine receptor blocker (8-PT) or a selective A1-receptor blocker (DPCPX). Although RTN injections of 8PT, DPCPX or the ectonucleotidase inhibitor ARL67156 did not affected baseline breathing in either anesthetized or awake rats. We did find that RTN application of DPCPX or ARL67156 potentiated the respiratory frequency response to CO2, suggesting a portion of ATP released in the RTN during high CO2/H+ is converted to adenosine and serves to limit chemoreceptor function. These results identify adenosine as a novel purinergic regulator of RTN chemoreceptor function during hypercapnia.

Keywords: Adenosine; Breathing; Central chemoreflex; Purinergic signaling; RTN.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / administration & dosage
  • Adenosine / metabolism*
  • Animals
  • Chemoreceptor Cells / drug effects
  • Chemoreceptor Cells / metabolism
  • Hypercapnia / drug therapy
  • Hypercapnia / metabolism*
  • Male
  • Medulla Oblongata / drug effects
  • Medulla Oblongata / metabolism*
  • Purinergic P1 Receptor Antagonists / pharmacology
  • Rats, Wistar
  • Receptors, Purinergic P1 / metabolism*
  • Reflex / drug effects
  • Reflex / physiology*
  • Respiration* / drug effects
  • Wakefulness


  • Purinergic P1 Receptor Antagonists
  • Receptors, Purinergic P1
  • Adenosine